Primary Biliary Cirrhosis
Primary Biliary Cirrhosis (PBC) is a chronic autoimmune disease of the liver where a persons medium-sized bile ducts become inflamed. When this happens the bile backs up into the liver damaging liver cells and results in scarring of the liver. This scarring reduces liver function and blood flow from the intestine to the heart [1]. Symptoms of PBC There are many symptoms that are associated with PBC some of them include jaundice skin, darkening of skin that is not from the sun, dry mouth and eyes, pain in abdomen, itchy skin, fatique, swollen feet and ankles, fluid accumulation in abdomen, greasy diarrhea, and fatty deposits on skin [8]. Stages of PBC There are four stages of PBC. The first stage is called the portal stage. This is when inflammations around the protal begins, there is very little damage to the bile duct, and no damage to the traids. Granulomas can often be detected at this stage for diagnosis purposes. Stage two is referred to as the periportal stage. The triads start to become enlarged because the periportal become fibrous and inflamed. This is when small bile ducts begin to form. The septal stage is the third stage and there are active and passive fibrous septa present. Finally the fourth stage is called biliary cirrhosis where nodules become present [7]. Diagnosis and Treatment PBC is a life long disease that often does not show any symptoms. In many cases a routine liver test will detect PBC however many tests must be done to confirm the diagnosis. One of these such tests looks for antimitochondrial antibodies (AMA) in the blood, and when positive it is a strong indication that the patient has PBC. Other tests include ultrasounds and a liver biopsy [1]. A person can never fully be free of PBC unless they have a liver transplant however drugs like ursodiol can be taken daily to improve the persons liver function. Ursodiol works because it contains urseodeoxycholic acid which is a substance that naturally occurs in the bile [1]. Loci There are many loci associated with the autoimmune disease PBC. In a report done by 23andme there were three genes with corresponding SNP's that increase the risk that Professor Burke could have this autoimmune disease 3. These are: 1. Gene or region: IRF5 SNP: rs10488631 Genotype: Heterozygous CT - This SNP is located at the 3' end of the IRF5 gene. It has been thought to cause the autoimmune disease lupus erthymatosus as well as primary biliary cirrhosis when the C allele is present [4]. The primary risk allele for PBC is allele C. Professor Burke is heterozygous for the allele however if he were homozygous his odds of having the disease would increase by 1.6 times [4]. 2. Gene or region: IL12A SNP: rs574808 Genotype: Homozygous CC -This SNP is associated with with HLA, IL12A, and IL12RB2 loci variants, which are known to have a strong association with the autoimmune disease PBC [2] [5]. 3. Gene or region: SPIB SNP: rs3745516 Genotype: Homozygous AA -This SNP is associated with variants at IRF5-TNPO3, 17q12-21 and MMEL1 loci [6]. With each A allele present in a genotype the individual has a 1.46 times higher odds of having PBC [6]. A study by Hirschfield, G.M., et al. recruited people from Canada and the USA to identify SNPs associated with PBC. This study included 857 individuals with PBC that were of European descent and 3,198 controls that were also of European descent. They identified the IRF5-TNPO3, 17q12-21 and MMEL1 loci as new risk loci for the autoimmune disease PBC. The IRF5-TNPO3 (encoding interferon regulatory factor 5 and transportin 3) locus helps to regulate roles for IRF5. It has also been linked to such disease like lupus erythematosus, systemic sclerosis, and Sjögrens syndrome. Changes in the IRF5 expression are also correlated with the alleles rs12539741 and rs2070197 [2]. The 17q12-21 locus is associated with diseases like asthma, Crohn's disease, and type 1 diabetes. It was most strongly associated with PBC through the ZPBP2 SNP, rs11557467[2]. Finally, the MMEL1 locus on chromosome 1p36 showed that SNPs rs3890745 and rs3748816 were associated with PBC. The SNP rs3748816 results methionine-to-threonine substitution, and the SNP rs3890745 is also associated with celiac disease and rheumatiod arthritis [2]. I found it interesting that this study looked at people in the Us and Canada with European decent. I wondered why this was and then I found a article by Kristen Boonstra, et al. that showed the geographic incidence of the disease out of 100,000 people in a population from areas around the world. This study showed a graph and it was clear that in the UK and Canada there are more people who present with the disease (see graph below) [9]. References 1. American Liver Foundation, Primary Biliary Cirrhosis, 2013. link: http://www.liverfoundation.org/abouttheliver/info/pbc/ 2. Hirschfield, G.M. et al., (2010). Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis, Nat Genet. 42(8):655-657. link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929126/ 3. 23andme.com, Professor Burke Profile on Primary Biliary Cirrhosis, 2013 4. SNPedia, 2013, http://snpedia.com/index.php/Rs10488631 5. SNPedia, 2013, http://snpedia.com/index.php/Rs574808 6. SNPedia, 2013, http://snpedia.com/index.php/Rs3745516 7. Wikipedia, 2013, Primary Biliary cirrhosis. link: http://en.wikipedia.org/wiki/Primary_biliary_cirrhosis 8. Mayo Clinic, 2013, http://www.mayoclinic.com/health/primary-biliary-cirrhosis/DS00604/DSECTION=symptoms 9. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: A systematic review written by Kristen Boonstra, et al. (2012) link: http://www.sciencedirect.com/science/article/pii/S0168827812000438